Citation
Plug, I. (2005, September 6). Hemophilia on the treshold of the 21st century. Retrieved from https://hdl.handle.net/1887/3389
Version: Corrected Publisher’s Version
License: Licence agreement concerning inclusion of doctoral thesis in theInstitutional Repository of the University of Leiden Downloaded from: https://hdl.handle.net/1887/3389
Hepati
ti
s C i
nfecti
on among Dutch haemophi
l
i
a
pati
ents: a nati
onwi
de cross-secti
onal
study i
nto
preval
ence and anti
vi
ral
treatment
Summary
Hepatitis C is a major co-morbidity among patients with haemophilia who received inadequately or non-virus inactivated clotting factor concentrates before 1992. The objectives of this study were to investigate the prevalence of hepatitis C and the use of antiviral therapies during the last decade among patients with haemophilia in the Netherlands.
W e performed a cross-sectional study and a questionnaire was sent to all 1519 patients known with haemophilia in the Netherlands between 2001 and 2002. The study population for the present study consisted of 771 patients who had received clotting factor products before 1992 of whom 638 reported their hepatitis C status.
In total 441 of the 638 (68%) patients ever had a positive test for hepatitis C virus (HCV); 344 patients (54%) had a current infection, and 97 (15%) had cleared the virus. Among 344 patients currently HCV infected, 111 (32%) had received treatment for hepatitis C, while 34% (33/97) of patients with an infection in the past had been treated for hepatitis C.
Introduction
Haemophilia is an X-linked bleeding disorder caused by a partial or complete lack of clotting factor activity: factor VIII in haemophilia A and factor IX in haemophilia B. Since the 1960s haemophilia patients have received intravenous factor VIII and IX replacement therapy1. In the following years it became apparent that viruses like Human Immunodeficiency Virus (HIV) and hepatitis C virus (HCV), formerly known as non-A non-B hepatitis, were
transmitted due to transfusion of infected plasma products2,3. Patients treated with large pool products were infected with HCV in 98%, whereas patients treated with cryoprecipitate were infected in 66% of the cases4. In the early 1990s, methods were developed to adequately inactivate HCV and subsequently donor screening for HCV was introduced, resulting in HCV safe clotting products4-6.
Materials and methods
Setting
Data for the present study were collected within the last survey of a series initiated by
Veltkamp in 197220. Since then nationwide surveys were repeated in 1978, 1985, 1992 and in 200121-24. These studies aimed to assess the medical and social consequences of haemophilia in the Netherlands. In 2001, postal questionnaires were sent to all 1519 patients known with haemophilia in the Netherlands, who were either registered at the Netherlands Hemophilia Patients Society, at the haemophilia treatment centres or known from previous surveys. In this last survey items on hepatitis C were added for the first time.
Data
To assess the validity of the self-reported items on hepatitis C, a random sample of 92 patients (14%) was taken from the two largest participating centres verifying their reported hepatitis C status with information from their treating haematologist.
Statistics
Infection with HCV was defined as three possible status: never infected with HCV, HCV infection cleared and chronic hepatitis C. 'Never infected with HCV' was defined as negative for both HCV antibodies and HCV-RNA in serum. A 'cleared HCV infection'or 'infection in the past' was defined as positive for HCV antibodies but negative for HCV-RNA. 'Chronic hepatitis C' was defined as positive for both HCV antibodies and HCV-RNA. In addition, 'ever infected with HCV' was defined as positive for HCV antibodies, regardless of the HCV RNA result.
To study risk of infection according to period of treatment, a sub-analysis was performed comparing infection rates between patients first treated before 1985 with patients first treated between 1985 and 1992. Patients with incomplete treatment history were excluded for this sub-analysis.
Results
A flow chart of the selection of patients for this study is shown in Fig. 1.
Fig. 1. Flowchart of selection of study population. Not tested for HCV, n=57
Did not know test result, n=56 No response, n=11 No test result n=9 Current infection with HCV n=344 HCV infection in the past n=97 Never infected with HCV n=197 HCV test result n=638 Tested for HCV n=647 Treated with clotting factor products
before 1992 n=771 70% response to questionnaire
n=1066 All known hemophilia
patients in the Netherlands
The response to the questionnaire was 1066 of 1519 (70%). General characteristics of the participants are shown in Table 1.
Table 1. Patient characteristics*
Total number of patients 638
Age in years 41 (10-87) Haemophilia type A B 557 (87%) 81 (13%) Severity of Haemophilia Mild Moderate Severe 211 (33%) 112 (18%) 315 (49%) Patients treated before 1985† 523 (82%)
HIV positive 28 (5%)
Patients treated before 1992‡ 638 Anti HCV positive
HCV RNA positive
441 (68% of tested patients) 344 (54% of tested patients)
* Information of patients treated before 1992 with a reported HCV test result. Values are medians (range) or numbers (percentage)
† At risk for HIV infection due to not adequately or non-virus inactivated clotting factor products ‡ At risk for HCV infection due to not adequately or non-virus inactivated clotting factor products
Hepatitis C
Patients treated with clotting products before 1992
HCV status. Among the 133 patients at risk without a HCV test result, 68% had mild haemophilia.
In the verification sample, 92% (85/92) reported their hepatitis C status correctly; 96% of patients with an HCV infection and 88% of patients with a cleared infection or those who where never infected.
Among 638 patients treated with clotting factor products before 1992 and tested for HCV, 441 (68%) ever had an anti-HCV positive test; 344 (54%) reported to be currently infected with HCV, 97 (15%) reported an infection in the past and 197 patients (31%) had never been infected. No infections with HCV occurred in patients who were treated after 1992 only. HCV infection was related to type of haemophilia; patients with haemophilia B had been infected more often than those with type A (84% vs. 67%, P < 0.01). Among patients at risk for HCV transmission, patients with severe haemophilia had the highest prevalence of hepatitis C (severe 65%, moderate 53%, mild 37%, P < 0.001).
The mean age of patients differed according to severity of haemophilia and HCV status; patients with severe haemophilia, who were never infected, were younger (mean age 23 years, 95% confidence interval (CI) 19-28) than both patients with severe haemophilia who cleared HCV (37 years, CI 33-41), and those currently infected (43 years, CI 41-45).
Infection rate of HCV according to treatment period
HIV infection
The prevalence of HIV infection among patients treated before 1985 and reporting their HIV status was 5% (28/523).
Treatment of hepatitis C
Among the 344 patients with a current HCV infection, 68% (233) had not been treated with antiviral drugs. The main reasons for refraining from therapy were shrinking from side effects (46%), normal liver function tests (45%) and expected low effectivity (35%). Other reported reasons were: doctor not convinced of benefit of treatment (19%), treatment not discussed by doctor (18%) and lack of time among patients (9%). Over the last decade, the proportion of patients having been treated is increasing (Fig. 2).
1990
1992
1994
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1998
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2002
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60
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100
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Treatment for HCV was completed among 128 patients and successful treatment was
reported in 26% (33/128). Sixteen patients were currently on combination therapy of IFN and ribavirin. Among patients who finished therapy, 57 patients were treated with IFN
monotherapy, 51 patients with the combination of IFN and ribavirin, while 13 patients were first treated with monotherapy and later retreated with combination therapy. Seven patients did not remember their treatment regimen.
Patients reported side effects of antiviral therapy in 84% (121/144). Fatigue (78%), flu-like symptoms (73%), and depressive symptoms (46%) were most frequently reported. In 15% of treated patients therapy was discontinued because of side effects.
Discussion
We report on a nationwide survey on the current prevalence of hepatitis C in haemophilia patients. Of 771 patients at risk for HCV infection, 638 reported their hepatitis C status. Fifty four per cent of tested patients reported to be currently infected with HCV, of whom 32% had been treated with antiviral therapy.
that, most patients with haemophilia are well informed about their disease and its complications21.
In this study, 68% of all tested patients potentially exposed to insufficiently viral inactivated clotting factor products had ever been infected with HCV and 54% of them reported a current HCV infection. The prevalence of hepatitis C in this population is similar to that reported by others4,9,25. As expected, the prevalence was highest among patients with severe haemophilia due to a higher number of exposures to clotting products than patients with mild or moderate disease. Haemophilia B was associated with a higher HCV infection rate (84% vs. 67%) due to exclusive treatment with large pool plasma products, whereas patients with haemophilia A were in many cases exclusively treated with small pool cryoprecipitate26. Confirming data in a Dutch study on 316 patients, reported HCV infection rates of 66% and 98% in patients exclusively treated with small pool cryoprecipitate and patients treated with large pool products, respectively4. In addition, the proportion of patients with severe haemophilia was higher among patients with haemophilia B than in those with haemophilia A (58% vs. 48%), with concomitant higher exposure rates to potentially unsafe clotting factor products.
Although there has been a trend towards starting treatment of HCV infection, so far only 32% of the HCV infected patients reported use of antiviral therapy, with a success rate of 26%. The main reasons for refraining from antiviral therapy were expected low effectivity of therapy, normal liver function tests and expected side effects. The argument of low expected effectivity loses its strength as treatment with PegIFN and ribavirin results in a sustained response in 50- 90% in treatment naive patients dependent on viral genotype18. It has been suggested that refraining from therapy in case of normal liver function tests may be
appropriate in patients with genotype 1 and 4 with normal histology at liver biopsy30. But this is inappropriate in patients with HCV genotype 2, 3 and 5, of whom 90% will achieve a sustained response.
Fatigue, flu-like symptoms and depression were the most frequently reported adverse events of antiviral therapy; this is in accordance with other reports17. Depression has been a common indication for dose reduction or even discontinuation of therapy17,31. Discontinuation of therapy due to adverse effects was reported in 15% in this study and was similar to that reported by others18,19,32,33.
The reported reasons for refraining from antiviral therapy indicate that there are still
uncertainties about long-term complications of hepatitis C and effectivity of antiviral therapy. Therefore, patients need to be fully informed about HCV infection, its consequences,
possibilities of treatment, and its effectivity.
In summary, this study shows that hepatitis C is still a major comorbidity in the Dutch
Acknowledgements
References
1. Nilsson IM, Berntorp E, Lofqvist T, Pettersson H: 25 Years Experience of Prophylactic Treatment in Severe Hemophilia-A and Hemophilia-B. Journal of Internal Medicine 1992;232:25-32.
2. Possible transfusion associated acquired immune deficiency syndrome (AIDS)-California. MMWR Morb Mortal Wkly Rep 1982;31:652-654.
3. Bamber M, Murray A, Kernoff PBA, Thomas HC: Short Incubation Non-A, Non-B Hepatitis Transmitted by Factor-VIII Concentrates in Patients with Congenital Coagulation Disorders - A Preliminary-Report of An Antigen-Antibody System. Medical Laboratory Sciences 1981;38:373-378.
4. Mauser-Bunschoten EP, Bresters D, van Drimmelen AA, Roosendaal G, Cuypers HT, Reesink HW, van der Poel CL, van den Berg HM, Lelie PN: Hepatitis C infection and viremia in Dutch hemophilia patients. J Med Virol 1995;45:241-246.
5. Fricke WA, Lamb MA: Viral Safety of Clotting Factor Concentrates. Seminars in Thrombosis and Hemostasis 1993;19:54-61.
6. Mannucci PM: Clinical-Evaluation of Viral Safety of Coagulation Factor-VIII and Factor-IX Concentrates. Vox Sanguinis 1993;64:197-203.
7. Lee C, Dusheiko G: The natural history and antiviral treatment of hepatitis C in haemophilia. Haemophilia 2002;8:322-329.
8. Lee CA: Hepatitis C infection and its management. Haemophilia 2000;6:133-137.
9. Yee TT, Griffioen A, Sabin CA, Dusheiko G, Lee CA: The natural history of HCV in a cohort of haemophilic patients infected between 1961 and 1985. Gut 2000;47:845-851.
10. Franchini M, Rossetti G, Tagliaferri A, Capra F, de Maria E, Pattacini C, Lippi G, Lo Cascio G, de Gironcoli M, Gandini G: The natural history of chronic hepatitis C in a cohort of HIV-negative Italian patients with hereditary bleeding disorders. Blood 2001;98:1836-1841.
11. Poynard T, Bedossa P, Opolon P: Natural history of liver fibrosis progression in patients with chronic hepatitis C. Lancet 1997;349:825-832.
12. Barr RD, Saleh M, Furlong W, Horsman J, Sek J, Pai M, Walker I: Health status and health-related quality of life associated with hemophilia. American Journal of Hematology 2002;71:152-160.
13. Hoofnagle JH, Mullen KD, Jones DB, Rustgi VK, Dibisceglie AM, Peters MG, Waggoner JG, Park Y, Jones EA: Treatment of Chronic Non-A Non-B Hepatitis with Recombinant Human Alpha-Interferon. Hepatology 1986;6:1220.
17. Fried MW: Side effects of therapy of hepatitis C and their management. Hepatology 2002;36:S237-S244.
18. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL, Haussinger D, Diago M, Carosi G, Dhumeaux D, Craxi A, Lin A, Hoffman J, Yu J: Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. New England Journal of Medicine 2002;347:975-982.
19. Manns MP, McHutchison JG, Gordon S, Rustgi V, Shiffman ML, Lee WM, Ling ML, Cort S, Albreacht JK: Peginterferon alfa-2b plus ribavirin compared to interferon alfa-2b plus ribavirin for the treatment of chronic hepatitis C: 24 week treatment analysis of a multicenter, multinational phase III randomized controlled trail. Hepatology 2000;32:297A.
20. Veltkamp J.J, Schrijver G, Willeumier W, van der Putte B, van Dijck H: Hemophilia in the Netherlands. Results of a survey on the medical, genetic and social situation of Dutch hemophiliacs. Acta Med Scand Suppl 1974;572:3-24.
21. Plug I, van der Bom JG, Peters M, Mauser-Bunschoten EP, Goede-Bolder A, Heijnen L, Smit C, Rijkom JEFZ, Willemse J, Rosendaal FR: Thirty years of hemophilia treatment in the Netherlands, 1972-2001. Blood 2004;104:3494-3500.
22. Rosendaal FR, Varekamp I, Smit C, Bröcker-Vriends AH, van Dijck H, Vandenbroucke JP, Hermans J, Suurmeijer TP, Briët E: Mortality and causes of death in Dutch haemophiliacs, 1973-86. Br J Haematol 1989;71:71-76.
23. Study group Haemophilia in The Netherlands. Haemophilia in the Netherlands 2; Results of a Survey carried out in 1978.
24. Triemstra M, Rosendaal FR, Smit C, Van der Ploeg HM, Briët E: Mortality in patients with hemophilia. Changes in a Dutch population from 1986 to 1992 and 1973 to 1986. Ann Intern Med 1995;123:823-827.
25. Brettler DB, Alter HJ, Dienstag JL, Forsberg AD, Levine PH: Prevalence of Hepatitis-C Virus-Antibody in A Cohort of Hemophilia Patients. Blood 1990;76:254-256.
26. Pool J.G, Gershgold E.J, Pappenhagen A.R: High-potency Antihaemophilic Fctor Concentrate prepared from Cryoglobulin Precipitate. Nature 1964;203:312.
27. Guo ZP, Yu MW: Hepatitis-C Virus-Rna in Factor-Viii Concentrates. Transfusion 1995;35:112-116.
28. Kernoff PBA, Miller EJ, Savidge GF, Machin SJ, Dewar MS, Preston FE: Reduced Risk of Non-A, Non-B Hepatitis After A 1St Exposure to Wet Heated Factor-Viii Concentrate. British Journal of Haematology 1987;67:207-211.
29. Schimpf K, Mannucci PM, Kreutz W, Brackmann HH, Auerswald G, Ciavarella N, Mosseler J, Derosa V, Kraus B, Brueckmann C, Mancuso G, Mittler U, Haschke F, Morfini M: Absence of Hepatitis After Treatment with A Pasteurized Factor-Viii Concentrate in Patients with Hemophilia and No Previous Transfusions. New England Journal of Medicine 1987;316:918-922.
31. Gallegos-Orozco JF, Fuentes AP, Argueta JG, Perez-Pruna C, Hinojosa-Becerril C, Sixtos-Alonso MS, Cruz-Castellanos S, Gutierrez-Reyes G, Olivera-Martinez MA, Gutierrez-Ruiz MC,
Kershenobich D: Health-related quality of life and depression in patients with chronic hepatitis C. Archives of Medical Research 2003;34:124-129.
32. McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, Goodman ZD, Ling MH, Cort S, Albrecht JK: Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med 1998;339:1485-1492.
